Environment International 165 (2022) 107321

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Full length article

Widespread pesticide contamination of drinking water and impact on

cancer risk in Brazil
Carolina Panis a, b, *, Luciano Zanetti Pessôa Candiotto c, Shaiane Carla Gaboardi d,
Susie Gurzenda e, Jurandir Cruz b, f, Marcia Castro e, Bernardo Lemos b, *
a
Laboratory of Tumor Biology, State University of Western Paraná, UNIOESTE, Francisco Beltrão, Paraná, Brazil
b
Department of Environmental Health, Harvard TH Chan School of Public Health, Boston, MA, United States
c
Territorial Studies Group (GETERR), State University of Western Paraná, UNIOESTE, Francisco Beltrão, Paraná, Brazil
d
Catarinense Federal Institute of Science and Technology, Campus Ibirama, Santa Catarina, Brazil
e
Department of Global Health and Population, Harvard TH Chan School of Public Health, Boston, MA, United States
f
Faculty of Medicine of the University of São Paulo, São Paulo, Brazil

A R T I C L E I N F O A B S T R A C T

Handling Editor: Adrian Covaci Pesticides, which are associated with endocrine dysfunction, immunological dysregulation, and cancer, are
widespread sources of drinking water contamination. The state of Paraná has a population of 11 million, is the
Keywords: second largest grain producer in Brazil and is a leading consumer of pesticides. In this study, we analyzed the
Drinking water extent of drinking water contamination from 11 proven, probable, or potentially carcinogenic pesticides (ala­
Pesticides
chlor, aldrin-dieldrin, atrazine, chlordane, DDT-DDD-DDE, diuron, glyphosate-AMPA, lindane-γ-HCH,
Contamination
mancozeb-ETU, molinate, and trifluralin) in 127 grain-producing municipalities in the state of Paraná. Extensive
Cancer
contamination of drinking water was found, including legacy pesticides such as aldrin-dieldrin (mean 0.047
ppb), DDT-DDD-DDE (mean: 0.07), chlordane (mean: 0.181), and lindane-HCH (mean: 2.17). Most of the mu­
nicipalities were significantly above the maximum limits for each one of the currently allowed pesticides (67%
for alachlor, 9.44% for atrazine, 96.85% for diuron, 100% for glyphosate-AMPA, 80.31% for mancozeb-ETU,
91.33% for molinate, and 12.6% for trifluralin). Ninety-seven percent of municipalities presented a sum of all
pesticides at levels significantly above (189.84 ppb) the European Union preconized limits (<0.5 ppb). Using the
mean pesticide concentration in water (ppb), the exposed population for each municipality, and the benchmark
cancer risk for pesticides, we estimated the minimum number of cancer cases attributable to pesticide-
contaminated drinking water during the period (total of 542 cases). More than 80% were attributed to
mancozeb-ETU and diuron. Glyphosate-AMPA and diuron-attributable cases strongly correlated with the total
cancer cases in the same period (R = 0.8117 and 0.8138, respectively) as well as with breast cancer cases (R =
0.7695 and 0.7551, respectively). Water contamination was significantly correlated with the sum of the esti­
mated cancer cases for all 11 pesticides detected in each city (R = 0.58 and p < 0.0001). These findings reveal
extensive contamination of drinking water in the state of Paraná and suggest that contamination may increase
the risk of cancer in this region.

1. Introduction Moreover, approximately 80% of the pesticides authorized for

commercialization in Brazil are prohibited in at least three countries of
Environmental pesticide contamination is a global health concern, the Organization for Economic Cooperation and Development (OECD)
especially in Brazil, given its status as one of the largest pesticide con­ of the European community and have resulted in more than 70,000
sumers in the world as well as its permissive regulatory control. The intoxications (Panis et al., 2022a).
country consumes more than 500 thousand tons of these substances per Uncontrolled pesticide use may cause large-scale environmental
year, resulting in an annual pesticide consumption of 7 L per capita. contamination, including the contamination of water, soil, air, plants,

* Corresponding authors at: Laboratory of Tumor Biology, State University of Western Paraná, UNIOESTE, Francisco Beltrão, Paraná, Brazil (C. Panis). Department
of Environmental Health, Harvard TH Chan School of Public Health, Boston MA, USA. (Bernardo Lemos).
E-mail addresses: [email protected] (C. Panis), [email protected] (B. Lemos).

https://doi.org/10.1016/j.envint.2022.107321
Received 14 February 2022; Received in revised form 26 April 2022; Accepted 23 May 2022
Available online 3 June 2022
0160-4120/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
C. Panis et al. Environment International 165 (2022) 107321

animals, food products, and humans. These substances can reach aquatic According to the National Cancer Institute (INCA), Paraná is among
systems through runoff from pulverized crops, reducing the potability of the top five states with the highest cancer incidence in the country,
water for human consumption (Aydinalp and Porca, 2004). In addition, particularly for certain types such as colon, lung, breast, and oral cancers
the soil matrix acts as pesticide storage because of its high capacity to (INCA, 2020). Contamination of drinking water by pesticides has been
interact with such substances (Syafrudin et al., 2021). Despite their loss extensively documented worldwide. However, results regarding pesti­
by microbial degradation and soil adsorption, pesticides are frequently cide consumption (or exposure) and their association with cancer risk
reported as contaminants in drinking water. are inconclusive (Oller-Arlandis and Sanz-Valero, 2012; Inoue-Choi
The European Union (EU) standards of drinking water safety levels et al., 2016) or divergent (Wong et al., 1989; Van Leeuwen et al.,
follow the precautionary principle in environmental science (Kriebel 1999; Buczyńska and Szadkowska-Stańczyk, 2005; McElroy et al, 2007)
et al., 2001), and are considered a reference for human health and Most of these studies investigated populations with a small group of
environmental protection. According to the EU Drinking Water Direc­ exposed individuals, which may be a relevant limitation in research
tive, the sum of the maximum allowable concentration of pesticides in concerning the relationship between pesticides in drinking water and
drinking water is 0.1 µg/L (Dolan et al., 2013). Despite this, pesticide cancer risk.
levels in drinking water are commonly above the EU preconized limits Here, we evaluated evidence regarding pesticide contamination in
because of their capacity for persistence in the environment. the drinking water of municipalities in the state of Paraná. We estimated
For example, legacy pesticide residues have been reported as the cancer risk for approximately 5 million people exposed to pesticides
drinking water contaminants worldwide (EPA, 2021). Organochlorine found as contaminants in drinking water that present some carcinogenic
pesticides, such as aldrin-dieldrin, DDT-DDE, and HCH isomers, are potential according to the IARC classification. We also investigated the
among the major persistent organic pollutants (POPs) owing to their correlation between drinking water contamination, cancer cases re­
high toxicity and persistence (Hung and Thiemann, 2002; Kaushik et al., ported by INCA during the same period, and pesticide trade for the
2010; Aydin et al., 2013; Agarwal et al., 2015; Rodríguez et al., 2017). chemicals currently allowed in the state.
Similar results have been reported for currently allowed pesticides, such
as glyphosate (Van Stempvoort et al., 2016; Tang et al., 2015), with 2. Methods
acceptable levels in drinking water being 5000 times higher in Brazil
than in the European Union (EU) (Bombardi, 2019). This study was based on the SISÁGUA Report for drinking water
The consequences of lifetime human exposure to pesticides have quality in Paraná from 2014 to 2017 (available at https://dados.gov.
been drawing increased attention because of their potential impact on br/dataset; SISÁGUA, 2021). The complete supporting database
health, and the risks to human health have been documented (Yi et al., extracted from SISÁGUA is shown in Supplementary Table 1. SISÁGUA
2019; Zhang et al., 2020; Pizzatti et al., 2020; Zhang et al., 2021; Panis is a report of the National Program for the Monitoring of the Quality of
et al., 2022b). For instance, the Agricultural Health Study, a consortium Water for Human Consumption (VIGIÁGUA), which consists of a set of
focused on understanding the impact of human exposure to mixed actions that aim to guarantee safe drinking water for population con­
pesticides, documented health outcomes associated with chronic pesti­ sumption, compatible with the standards preconized by Brazilian
cide exposure (AHS, 2021). The consequences of exposure include legislation (Candiotto et al., 2017). As part of VIGIÁGUA, 27 pesticides
increased risk for thyroid dysfunction, including cancer (Hoffmann were monitored in drinking water, including those currently traded in
et al., 2021, Shrestha et al., 2018), risk of hematological cancers and the country, as well as some banned pesticides that are classified as
their precursor conditions (Lerro et al., 2021; Andreotti et al., 2018), persistent organic pollutants. The tracked pesticides were 2,4-dichloro­
altered kidney function and risk of renal carcinoma (Shearer et al., 2021; phenoxyacetic acid- 2,4,5-Trichlorophenoxyacetic acid (2,4D-2,4,5T),
Andreotti et al., 2020), high Parkinson’s disease incidence (Shrestha alachlor, aldicarb, aldrin, atrazine, carbendazim, carbofuran, chlordane,
et al., 2020), female hormone disruption (Farr et al., 2004) and evidence chlorpyrifos dichlorodiphenyltrichloroethane-dichlorodiphenyldichloro
of immune disorder occurrence (Parks et al., 2019; Cooper et al., 2004). ethylene-dichlorodiphenyldichloroethylene (DDT-DDD-DDE), diuron,
Human health benchmarks for pesticides have been proposed as a endosulfan, endrin, glyphosate-aminomethylphosphonic acid (AMPA),
strategy to ensure that pesticide concentrations in drinking water lindane-gamma-hexachlorocyclohexane (γ-HCH), mancozeb-ethyleneth
remain at a safe level and to protect the public against their carcinogenic iourea (ETU), methamidophos, metolachlor, molinate, parathion, pen­
potential (U.S. EPA, 2017). Therefore, regardless of their concentration dimenthalin, permethrin, prophenofos, simazine, tebuconazole, terbu­
in drinking water at any given time, pesticides are considered a potential fos, and trifluraline. For DDT, glyphosate, lindane, and mancozeb, by-
risk for cancer development due to their continuous ingestion. product levels have also been reported (DDD-DDE, AMPA, γ-HCH, and
In this context, a technical report published in 2018 by the Brazilian ETU, respectively).
Water Quality Surveillance Information System for Human Consump­ The study design is illustrated in Fig. 1. Based on data available in the
tion (SISÁGUA, 2021), the official agency responsible for water quality SISÁGUA report (from samples collected and analyzed between 2014
monitoring in Brazil, identified the presence of at least one of 27 and 2017) for Paraná, we included 127 municipalities, corresponding to
different pesticides in the drinking water of one in four Brazilian cities. approximately 5.5 million people and a coverage rate of 50% of the state
Five of these pesticides are categorized as probably carcinogenic to population. Paraná contains 399 municipalities, 326 of which had their
humans, indicating that these agents have strong carcinogenic potential, drinking water analyzed and reported by SISÁGUA. Among these, 127
according to the cancer classification proposed by both the United States (here analyzed) presented the quantification of at least one of the 11
Environmental Protection Agency (U.S. EPA, 2005) and the Interna­ pesticides listed by the International Agency for Research on Cancer
tional Agency for Research on Cancer (IARC, 2019). POPs DDT-DDD- (IARC, 2019) and the United States Environmental Protection Agency
DDE and lindane, along with currently allowed pesticides such as (U.S EPA, 2005) as probably or possibly carcinogens to humans: ala­
glyphosate, diuron and mancozeb, are amongst the residues detected. chlor, aldrin-dieldrin, atrazine, chlordane, DDT-DDD-DDE, diuron,
Some high-producing agricultural regions consume a large share of glyphosate-AMPA, mancozeb-ETU, molinate, and trifluralin, along with
the pesticides used in Brazil and may display substantially higher the proven carcinogenic pesticide lindane.
drinking water contamination. The state of Paraná is among the top We calculated the cancer risk level by estimating the number of
three food producing and pesticide consumers in Brazil (IBAMA, 2019; cancer cases attributable to each pesticide according to the following
Brovini et al., 2021; FAO, 2021). Given the permissive regulation of formula:
pesticide use in Brazil, it is possible that drinking water contamination
would be substantial and likely high above the regulatory thresholds [(Observed average pesticide ppb × number of individuals at risk)/ 106
benchmark cancer risk]
used in other regions of the world.

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C. Panis et al. Environment International 165 (2022) 107321

Fig. 1. Design of the study. From 2014 to 2017 the main water regulatory agency in Brazil (SISAGUA, http://sisagua.saude.gov.br/sisagua) tracked the contami­
nation of 27 pesticides in public drinking water. Out of these, 16 pesticides are putatively carcinogenic and 11 have a known benchmark cancer risk. From this data,
we excluded unquantifiable values and possible typos to calculated the average municipality contamination. Based on this information and demographic information,
we applied the benchmark concept to estimate the number of cancer-associated with drinking water contamination by pesticides in municipalities from Paraná State.
In the map, the mean pesticide trade of the 27 Brazilian States:Acre - AC; Alagoas - AL; Amapá - AP; Amazonas - AM; Bahia - BA; Ceará - CE; Distrito Federal - DF;
Espírito Santo - ES; Goiás - GO; Maranhão - MA; Mato Grosso - MT; Mato Grosso do Sul - MS; Minas Gerais - MG; Pará - PA; Paraíba - PB; Paraná - PR; Pernambuco -
PE; Piauí - PI; Roraima - RR; Rondônia - RO; Rio de Janeiro - RJ; Rio Grande do Norte - RN; Rio Grande do Sul - RS; Santa Catarina - SC; São Paulo - SP; Sergipe - SE;
Tocantins - TO. Paraná is among the top 5 pesticide traders of the country. The highlight shows the 127 cities of the state included in the study.

Where: (i) the observed average pesticide ppb = average drinking water selected because it is likely to be less affected by drinking water
contamination level in ppb for each chosen pesticide reported to each contamination than genetic factors.
selected municipality, (ii) the number of individuals at risk = number of Statistical analyses were conducted using GraphPad Prism software
individuals registered as residents for each municipality, and (iii) 106 (version 7.0; GraphPad, San Diego, CA, USA). Spearman correlations
Benchmark cancer risk = value estimated by the Office of Environmental were performed among ppb levels in drinking water for aldrin-dieldrin,
Health, Hazard Assessment, California Environmental Protection diuron, lindane-γ-HCH, and mancozeb-ETU; the volume of pesticide
Agency, Office of Environmental Health Hazard Assessment Air Toxi­ currently traded for each municipality; and the mean number of cancer
cology and Epidemiology Branch (OEHAA, 2009). This represents the cases reported by INCA. Statistical significance was set at p value < 0.05.
probability that an individual exposed to a determined pesticide will
develop cancer over a lifetime. 3. Results
As aldrin-dieldrin, diuron, lindane-γ-HCH, and mancozeb-ETU
together were responsible for almost 98% of the estimated cancer Pesticide contamination in drinking water was evaluated relative to
cases, further analyses considered only these pesticides. Diuron and the maximum limits allowed by Brazilian and European Union (EU)
mancozeb are currently allowed in Brazil, whereas aldrin-dieldrin and agencies as well as the benchmark cancer risk according to EPA/OEHAA
lindane-γ-HCH are banned. and the IARC/EPA cancer classification for the 11 selected pesticides
Aiming to investigate putative associations between the estimated (Table 1). Data concerning drinking water contamination for each
cancer cases related to drinking water contamination by the 11 selected pesticide and municipality were tabulated for the 2014–2017 period
pesticides and the number of consolidated cancer cases registered in (Supplementary Table 1; SISÁGUA, 2021). We calculated the average
Paraná, we obtained the total number of cancer cases registered in the municipality contamination, including only the values reported as equal
same period as the SISÁGUA report (2014–2017) from the National to or greater than the limit of quantification established for each sub­
Hospital Cancer Registry Information Hospital Tabulator (INCA, 2021). stance. Data are reported in comparison to the maximum allowable limit
The data included five specific cancers (bladder, breast, lung, thyroid, in drinking water set by regulatory agencies in Brazil and the EU
and ovarian) by year, municipality of origin, and primary tumor local­ (Table 1). Pesticide contamination in drinking water varies across 127
ization. The 2014–2017 average was calculated for each cancer type. We municipalities in Paraná State (Figs. 2 and 3). Three persistent organic
selected these five cancer types based on the literature. Diuron and pollutants (POPs), namely aldrin-dieldrin, chlordane, and DDT-DDD-
mancozeb have been reported to be associated with bladder and thyroid DDE, along with lindane-γ-HCH, are not currently allowed in Brazil,
cancer, respectively. Lung cancer (second most common among males) but remain present at concerning levels in some municipalities (Fig. 2).
and breast cancer (most common among females) were selected due to Aldrin-dieldrin levels ranged from 0.001 ppb to 3 ppb, with a mean
their high incidence in the Brazilian population. Ovarian cancer was concentration of 0.047 ppb. Seven municipalities (7.21%) had values

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C. Panis et al. Environment International 165 (2022) 107321

Fig. 2. Pesticide levels (ppb) in drinking water from 127 municipalities located at Paraná State, data for the persistent organic pollutants (POPs). Pesticide con­
centration is expressed in ppb, as informed in the SISÁGUA report. The graphs represent the mean ppb reported by SISAGUA 2014–2017 document for quantified
pesticides, and each dot represent one specific municipality. The lines indicate the maximum concentration allowed for each pesticide in Brazil (green line), US (blue
line) and Europe (red line).

equal to or higher than the maximum limit allowed in Brazil. All mu­ equal to or over the EU limits; three municipalities showed levels equal
nicipalities exceeded the maximum limit established by the EU. The to or greater than the Brazilian maximum limits. In the case of diuron,
mean concentration of chlordane was 0.181 ppb and four municipalities drinking water contamination ranged from 0.0007 to 90.05 ppb, and the
had values equal to or higher than the Brazilian maximum allowed limit. mean concentration was 73.53 ppb (735.3 times over EU limits). Only
Approximately 44% of the 127 cities had chlordane levels above EU four municipalities were under the EU recommended limits; the 75th
limits. Despite DDT-DDD-DDE being banned from Brazil in 1985, it was percentile showed a mean concentration of approximately 90 ppm,
detected in the drinking water from almost all municipalities analyzed which is the maximum limit allowed in Brazil (900 times over EU
with a mean concentration of 0.07 ppb – almost 7-fold the maximum EU limits). Glyphosate-AMPA was the only residue that had values below
limit. Two municipalities presented DDT-DDD-DDE water contamina­ the maximum limits allowed by Brazilian regulators in all municipalities
tion over the maximum limit allowed for Brazilian law (1 ppb). For analyzed by SISÁGUA. Values ranged from 0.12 to 282.5 ppb, with a
lindane-γ-HCH, values ranged from 0 to 180 ppb (1,800 times over the mean concentration of 74.79 ppb (747.9 times over EU limits). Ac­
EU limit of 0.1 ppb), with a mean concentration of 2.17 ppb (21.7 times cording to Brazilian regulations, the maximum glyphosate-AMPA limit
over the EU limit). Approximately 16% of municipalities had lindane- allowed for drinking water is 500 ppb, which is 5000-fold higher than
γ-HCH concentrations over the EU limit. A total of 64 municipalities the EU recommended limit.
(50.4%) had all four POPs concomitantly measured in drinking water, Almost 50% of the municipalities had all currently allowed pesti­
while only 18 (14.2%) did not have any POP detected. Furthermore, cides concomitantly detected in their drinking water, while only 18.9%
8.66% of municipalities were at or above the maximum limits for aldrin- did not show any of these pesticides. Diuron and mancozeb-ETU were
dieldrin (range 0.03–11 ppb), 3.15% for chlordane (range 0.2–15 ppb), the main contaminants detected at the Brazilian maximum allowed
1.6% for DDT-DDD-DDE (range 1–2 ppb) and 3.94% for lindane-γ-HCH concentrations (90 ppb for diuron and 180 ppb for mancozeb-ETU) in
(2–180 ppb). When considering the sum of all POPs studied, 32.3% of almost 52% of all municipalities studied, representing values 900 and
the municipalities presented levels over the limit of 0.5 ppb recom­ 1800 times above the European limit, respectively. Furthermore, 97% of
mended by the EU for drinking water safety. the included municipalities presented a sum of all pesticides at levels
Regarding the pesticides that are currently allowed (Fig. 3), alachlor above the EU recommended limits (sum over 0.5 ppb limit, mean of
concentrations ranged from 0 to 20 ppb (200 times over the EU limit of 189.84 ppb). Considering the EU limits, most municipalities were
0.1 ppb), with a mean concentration of 0.7 ppb. Values over the Bra­ significantly above the maximum limits for each of the currently allowed
zilian maximum limit were found in three municipalities. Most of the pesticides (67% for alachlor, 9.44% for atrazine, 96.85% for diuron,
analyzed samples were above the EU maximum limits. For atrazine, the 100% for glyphosate-AMPA, 80.31% for mancozeb-ETU, 91.33% for
values ranged from 0 to 2.5 ppb (25 times over EU limits), with a mean molinate, and 12.6% for trifluralin).
concentration of 0.16 ppb. A total of 12 municipalities showed levels Mancozeb-ETU contamination was found in several municipalities,

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C. Panis et al. Environment International 165 (2022) 107321

25 3 MCL US

20
2 MCL Brazil
15
10 MCL Brazil
1
5
MCL US
ppb

ppb
0.5 0.10 MCL EU

0.4 0.08
0.3 0.06
0.2 0.04
0.1 MCL EU 0.02
0.0 0.00
Alachlor Atrazine

150 MCL US MCL US

600
100 MCL Brazil
MCL Brazil
400
50
200
ppb

ppb
1.0 100
0.8
0.6
50
0.4
0.2
MCL EU MCL EU
0.0 0
Diuron Glyphosate-AMPA
200 8
MCL Brazil
6 MCL Brazil

150
4

2
ppb

ppb

100
1.0
0.8

50 0.6
0.4
0.2
0 MCL EU MCL EU
0.0
Mancozeb-ETU Molinate
20 MCL Brazil
15
10
5

1.0
0.8
ppb

0.6
0.4
0.2

0.010
0.008
0.006
0.004
0.002
0.000 MCL EU
Trifuralin

Fig. 3. Pesticide levels (ppb) in drinking water from 127 municipalities located at Paraná State, data for the currently allowed. Pesticide concentration is expressed in
ppb, as informed in the SISÁGUA report. The graphs represent the mean ppb reported by SISAGUA (2014–2017) for quantified pesticides, and each dot represent one
specific municipality. The lines indicate the maximum concentration allowed for each pesticide in Brazil (green line), US (blue line) and Europe (red line). For some
pesticides, the US allowed limit was not found.

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C. Panis et al. Environment International 165 (2022) 107321

ranging from 0 to 180 ppb (1,800 times over the EU limit of 0.1 ppb), Table 1
with a mean concentration of 121.4 ppb. The mean mancozeb level for Cancer risk-associated pesticides selected for investigation based on the United
the 75th percentile was 180 ppb, showing that most of the cities States Environmental Protection Agency (U.S. EPA) or the California Office of
included in the study presented the maximum limits allowed by Bra­ Environmental Health Hazard Assessment (OEHHA) categorization, maximum
zilian law. For molinate, the concentrations ranged from 0 to 6.25 ppb limits of pesticides in drinking water allowed by Brazilian and European Union
regulatory agencies, and cancer classification group for each one based on data
(mean 0.77 ppb, 7.7 times over EU limits), and two municipalities
from the International Agency for Research on Cancer (IARC) or EPA.
exhibited values equal to or higher than the allowable limits recom­
mended by Brazilian law. Trifluralin levels varied from 0 to 20 ppb (200 Pesticide Maximum Maximum Benchmark Carcinogenicity
limit limit cancer risk evidence
times the EU limits), and one municipality had a concentration at the
allowed - allowed – of 1 case/ classification
upper limit allowed by Brazilian law (São João do Ivaí, 20 ppb). Brazil European 106 people
Based on the average drinking water contamination and the bench­ (ppb) Union (EPA/
mark cancer risk according to EPA/OEHAA and the IARC/EPA cancer (ppb) OEHAA)
classification for the 11 selected pesticides (Table 1), we estimated 542 Alachlor 20 0.1 0.4 Probably
cancer cases per million people collectively attributable to the 11 pes­ carcinogenic to
ticides analyzed, across all municipalities (Fig. 4). Approximately 50% humans (IARC,
EPA)
of cases were attributable to mancozeb-ETU contamination (273 cases
Aldrin_dieldrin 0.03 0 0.002 Probably
per million), followed by diuron (178 cases), aldrin-dieldrin (43 cases), carcinogenic to
and lindane-γ-HCH (38 cases). humans (IARC,
Significant correlations between drinking water contamination (ppb) EPA)
Atrazine 2 0.1 0.15 Not classifiable as
and pesticide trade in tons were found in diuron and mancozeb
to human
(Table 2). Data about the 11 selected pesticides and their specific carcinogenicity
associated cancers are shown in Table 3. Cancer cases attributable to (IARC)
diuron and glyphosate-AMPA were strongly correlated with cancer cases Chlordane 0.2 0.01 0.1 Possibly
reported by INCA, particularly for the total number of cases (R = 0.8117 carcinogenic
(IARC, EPA)
and 0.8138, respectively) and breast cancer (R = 0.7695 and 0.7551,
DDT_DDD_DDE 1 0.01 0.1 Possibly
respectively) (Fig. 5 and Supplementary Table 2). Negative or weak carcinogenic
correlations were observed for ovarian cancer (R-values varying from (IARC, EPA)
− 0.2454 to 0.04030). Strong correlations were observed between Diuron 90 0.1 2 Probably
carcinogenic to
aldrin-dieldrin and glyphosate-AMPA levels. Mancozeb-ETU showed the
humans (IARC,
weakest correlation with most cancers. Overall, ovarian cancers showed EPA)
weak correlations with all pesticides, whereas breast cancers showed the Glyphosate + 500 0.1 56.45 Probably
strongest correlations. Significant positive correlations between the sum AMPA carcinogenic to
of lung, breast, thyroid, bladder, and ovarian cancer cases reported by humans(IARC)
Not Classifiable
INCA (total cases) and pesticide-attributable cancer cases were found for
as to Human
10 out of the 11 pesticides, excluding alachlor. Lung, thyroid, and Carcinogenicity
bladder cancers showed significant correlations with pesticide- (EPA)
attributable cancer cases (8 out of 11 pesticides), whereas for breast Lindane - HCH 2 0.1 0.032 Carcinogenic to
cancer, this significance was observed in 9 out of 11 pesticides. humans (IARC,
EPA)
Regarding each pesticide, alachlor- and mancozeb-attributable cancer Mancozeb/ 180 0.1 0.06 (ETU) No data (IARC)
ETU Probably
carcinogenic
(EPA for ETU)
Molinate 6 0 1 Not classifiable as
to human
carcinogenicity
(IARC)
Trifluralin 20 0 4 Not classifiable as
to human
carcinogenicity
(IARC)
Possibly
carcinogenic
(EPA)

Notes: Classification. Source(s):1.EPA: https://www.epa.gov/sites/production/file

s/2018–03/documents/dwtable2018.pdf; and https://www.epa.gov/sites/produc
tion/files/2015–10/documents/hh-benchmarks-techdoc.pdf2. EPA(DDT): https://
cfpub.epa.gov/ncea/iris2/chemicalLanding.cfm?substance_nmbr = 147; 3.IARC:
https://monographs.iarc.fr/agents-classified-by-the-iarc/; 4.OEHHA: https://oehh
a.ca.gov/. EU Drinking Water Directive 98/83/EC: Drinking water legislation in
Europe is derived from the EU Drinking Water Directive which sets minimum
standards for various substances in water. For any individual pesticide the
maximum allowed at any time is 0.1 ppb (parts per billion) and the total for all
pesticides must not exceed 0.5 ppb. AMPA = aminomethylphosphonic acid; ETU =
Fig. 4. Total estimated cancer cases attributed to the contamination of drinking ethylenethiourea.
water for the 11 included pesticides evaluated in 127 municipalities from
Paraná State. The estimative was performed based on the mean concentration
of the pesticide in drinking water reported by SISÁGUA in the period from 2014
to 2017, considering its benchmark cancer risk and the number of
exposed people.

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C. Panis et al. Environment International 165 (2022) 107321

Table 2 of the pesticides identified here are proven carcinogens (e.g., lindane-
Correlations between the levels of pesticides in drinking water (ppb) versus the γ-HCH), probable carcinogens (e.g., alachlor, aldrin-dieldrin, diuron,
average trade of Mancozeb and Diuron, in the 127 municipalities in the state of glyphosate-AMPA, mancozeb-ETU), or endocrine disruptors (EDCs, such
Paraná in the analyzed period (2014–2017). as atrazine, mancozeb, and glyphosate), and cause significant changes in
Correlation Spearman r value (CI P value DNA, including mutations and epigenetic modifications (Kucka et al.,
95)% 2012; Axelstad et al., 2011; Lesseur et al., 2021; Kumar et al., 2020).
Diuron in drinking water (ppb) × Diuron trade 0.07268 (− 0.1413 to 0.4935 Brazil has relatively high maximum limits compared to those established
(tons) 0.2802) for the EU, ranging from 20-fold higher for atrazine and alachlor to
Mancozeb/ETU in drinking water (ppb) × 0.2221 (0.01434 to 0.0314* 5000-fold higher for glyphosate levels. The POPs aldrin-dieldrin and
Mancozeb trade (tons) 0.4115)
lindane-γ-HCH presented the greatest benchmark cancer risk (0.002 and
*
p < 0.05. 0.032, respectively), which means that very small concentrations of
these substances in drinking water are enough to contribute to increased
cancer risk. According to the IARC/EPA cancer classification, lindane-
Table 3 γ-HCH is the only substance described as a proven carcinogen, whereas
Mean pesticide levels in drinking water (ppb), the main use in Brazil, and cancer
chlordane and DDT-DDD-DDE were classified as possibly carcinogenic.
association according to IARC, EPA, and OEHAA agencies.
Finally, the EU allows a total sum of 0.5 ppb for all pesticides detected in
Pesticide Mean Main use in Cancer association drinking water, while in Brazil, there is no regulation for the maximum
concentration Brazila
allowed when all pesticides are considered together.
indentified
(ppb, min–max) Our findings indicate that pesticides currently sold and those banned
decades ago are widely detected as contaminants in the state’s water
Alachlor 0.69 (0–20) Herbicide Laryngeal cancer,
Sugar cane lymphohematopoietic
system. It was also observed that the levels of individual pesticides were
and corn (IARC) substantially above the safe limits recommended by the EU for practi­
crops Urinary tract (EPA) cally all municipalities analyzed. Thus, considering pesticides in
Aldrin_dieldrin 0.047 (0.001–3) Insecticide Breast (IARC) aggregate, all municipalities analyzed in the present study reached
Banished Liver (EPA)
pesticide levels above this value. We estimated the impact of drinking
Atrazine 0.16 (0–2.5) Herbicide Thyroid (OEHAA)
Sugar cane water contamination on the number of cancer cases attributable to 11
and corn pesticides with potential or proven carcinogenic activity, and the esti­
crops mates were correlated with cancer cases registered in Paraná for the
Chlordane 0.18 (0–15) Inseticide Liver (IARC and EPA)
same period.
Banished Thyroid (OEHAA)
DDT_DDD_DDE 0.07 (0–1) Inseticide Testis, liver and
Banished lymphoma (IARC) 4.1. POPs
Liver (EPA)
Diuron 73.53 Herbicide Kidney, lung (IARC) The water for human consumption in much of Brazil is contaminated
(0.001–90.05) Sugar cane Urinary tract (EPA)
and other
by pesticides, which has permissive legislation regarding the maximum
crops allowable limits compared to the EU. Desirable aldrin-dieldrin levels in
Glyphosate- 74.79 Herbicide Lymphoma (IARC, aquatic environments are reported by WHO as less than 0.01 ppb (WHO,
AMPA (0.12–282.5) soy, weat OEHAA) 2003); Brazil accepts 3 times higher levels as safe, whereas the EU sets
and corn
the safe level at zero. All the samples analyzed in our study exhibited
crops
Lindane-γHCH 2.17 (0–180) Inseticide Lymphoma (IARC) POP contamination. Aldrin-dieldrin has a half-life >5 years (EPA, 2003).
Banished Liver (EPA and OEHAA) Despite decades of global bans, aldrin-dieldrin has been documented in
Mancozeb-ETU 121.4 (0–180) Fungicide Thyroid (IARC) aquatic systems in heavy pesticide traders such as China, with maximum
Rice, soy and concentrations of 0.163 ppb for aldrin and 0.0233 ppb for dieldrin (Pan
other crops
Molinate 0.77 (0–6.25) Herbicide Urinary tract (OEHAA)
et al., 2019; Zhang et al., 2021). China and Brazil are among the top
Rice pesticide users, ranking first and third in the world, respectively (FAO,
Trifluraline 0.29 (0–20) Herbicide Lymphoma, thyroid, 2021). Comparatively, despite China’s average pesticide use per hectare
Cotton, rice, stomach, liver (IARC) of cropland, which is twice that registered for Brazil, the highest level of
sugar cane Urinary tract (EPA)
aldrin-dieldrin reported by SISÁGUA was 18- to 128-fold higher than
Notes: a Source: ADAPAR – Agência Paranaense de Defesa Agropecuária. For all that documented for China. This indicates that the capacity of pesticides
municipalities included, the sum of the total pesticide content is over the EU to reach drinking water systems in Brazil is considerable.
limits (0.5 ppb). The same situation has been documented for other POPs, confirming
that some regions in Brazil are probably among the most extensively
cases had less correlation with consolidated cancer cases than the other contaminated places worldwide (Wu et al., 2014). The maximum value
pesticides (one out of five correlations was significant). Aldrin-dieldrin, of DDT-DDD-DDE detected in our study was 1 ppb, which is the exact
atrazine, chlordane, DDT-DDD-DDE, diuron, glyphosate-AMPA, lindane, maximum limit allowed in Brazil, but 100 times the EU limit. DDT is
and trifluralin-attributable cancer cases showed significant correlations poorly soluble in water, causing it to bioaccumulate in the human body,
with consolidated cancer cases in four out of five topographies. and it has an estimated half-life of about 150 years in aquatic environ­
Concerning the impact of the 11 pesticide mixtures on cancer cases, a ments (Callahan et al., 1979). For lindane-γ-HCH, the maximum
significant correlation was found between the sum of the estimated observed contamination value corresponds to 1,800 times the EU limit.
cancer cases attributable to all 11 pesticides and the sum of the Historically, the state of Paraná has been a significant supplier of wood
consolidated cancer cases reported by INCA in the same period (R = 0.58 for export (Berger et al., 2007), and lindane was largely employed as a
and p < 0.0001, Supplementary Table 3). preservative in the past, before the institution of restrictive measures
against the use of this substance (IBAMA, 2006). Interestingly, lindane
4. Discussion residue is not ordinarily detected in surface water, where it is generally
removed by evaporation, and has an estimated half-life of approximately
Studies have investigated the cancer risk associated with pesticide two weeks (ABRAF, 2005; CDC, 2021). Therefore, its detection in
exposure in contaminated water worldwide (Pawlak et al., 2021). Some analyzed drinking water samples may reflect its leaching from

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C. Panis et al. Environment International 165 (2022) 107321

Fig. 5. Spearman correlation matrix between the estimated cancer cases versus the number of cancer cases reported by INCA for the 127 municipalities in Paraná
state in the period 2014–2017.

extensively contaminated soil, where its half-life and stability increase its levels in the drinking water of Paraná. Considering its high persis­
considerably. Furthermore, its detection in drinking water should be tence in the environment over 250 days (Rocha et al., 2013), and the
viewed with concern, since this compound is considered to be quite high levels observed in more than 90% of the studied municipalities, our
toxic. Studies worldwide have reported very low levels of DDT-DDD- findings suggest that Paraná drinking water has been severely contam­
DDE and lindane-γ-HCH residues in drinking water in several coun­ inated by multiple sources of mancozeb-ETU, such as polluted soil and
tries (Kuba et al., 2015; Aydin et al., 2013; Buczyńska and Szadkowska- direct entry into aquatic systems by careless manipulation and appli­
Stańczyk, 2005; Fatoki and Awofolu, 2004; Hung and Thiemann, 2002; cation of this product.
Kalajzic et al., 1998), highlighting the extent of water system contami­
nation by harmful legacy pesticides. 4.3. Pesticide exposure and cancer risk

4.2. Current use pesticides Three of the pesticides examined here (glyphosate-AMPA, diuron,
and mancozeb-ETU) are classified by the IARC as probable human car­
Regarding pesticides that are currently allowed in Brazil, all except cinogens (IARC, 2015, 2021). We observed that more than 80% of the
for atrazine and alachlor were detected at levels significantly higher municipalities had levels above the EU limit for at least one of these
than the recommended EU limits for practically all examined munici­ three pesticides, and all of them were above the EU limits for glyphosate-
palities. The observed levels of glyphosate-AMPA, mancozeb-ETU, and AMPA. The benchmark cancer risk is calculated for each substance
diuron were very high, reaching mean concentrations of >70 ppb each. based on the pesticide concentration needed to yield one case of cancer
Glyphosate is the most widely used pesticide in Brazil (IBAMA, for every 104 or 106 people over a 70-year interval of exposure. Aldrin-
2019), with glyphosate-AMPA safe levels in Brazil set at 5,000 times dieldrin offers the biggest carcinogenic risk (benchmark cancer risk of
above the safe levels recommended by the EU (Bombardi, 2019). Paraná 0.002), as compared to glyphosate-AMPA (benchmark cancer risk of
State, one of the largest producers of corn and soy in the world, stands 56.45).
out as the second main consumer of glyphosate in the country. Glyph­ Diuron, maconzeb-ETU, lindane-γ-HCH, and aldrin-dieldrin
osate accounts for almost 50% of pesticide trade in the state (Gaboardi accounted for almost 90% of the total estimated cancer cases attribut­
et al., 2019). This chemical has an estimated half-life of six hours able to pesticide consumption via contaminated drinking water.
(Connolly et al., 2019), and despite being complexed with organic Approximately 20% of cancer cases were credited to POPs contamina­
matrices present in aquatic systems, it has been detected at considerable tion. According to the EPA, aldrin-dieldrin is a probable carcinogen
levels in water samples worldwide, in association with its breakdown linked to breast and liver cancers (EPA, 2003). Experimental evidence
byproduct AMPA (Geng et al., 2021; Reynoso et al., 2020; Close et al., demonstrates that aldrin-dieldrin bioaccumulates in mammary tissue
2021). Most of these studies have reported lower levels of glyphosate (Gautam et al., 2020), and is positively associated with breast cancer
contamination than those found in the present study. Considering the risk among environmentally exposed populations because of its xen­
short half-life of glyphosate, it is possible that its levels oscillate sub­ oestrogen potential (Boada et al., 2012), especially in association with
stantially in water over time. other organochlorines (Jm et al., 2004). We found a significant corre­
Our results also showed that diuron and mancozeb-ETU could be lation between aldrin-dieldrin-estimated cancer cases and the number of
significant drinking water contaminants in Paraná. Data concerning breast cancer cases reported by the National Cancer Institute in the same
aquatic diuron contamination have indicated low levels in several period. Coincidentally, Paraná State registered higher rates of breast
countries worldwide despite continuous recommendations to avoid its cancer cases during the study period, with estimates above 25% of the
use (EU, 2000). Contamination has been reported at very low levels, national rates.
which may be related to its low water solubility. Mancozeb-ETU is the Lindane-γ-HCH is a proven carcinogen, and its ingestion in
fifth most traded pesticide in the state (ADAPAR 2021). Mancozeb is contaminated water and food increases the risk of cancer development
chemically unstable in aqueous systems, degrades quickly, and yields in both children and adults (Odewale et al., 2021; Woldetsadik et al.,
the final product ETU (López-Fernández et al., 2017). Little information 2021). We obtained a significant positive correlation between lindane-
is available regarding mancozeb-ETU as a contaminant of drinking γ-HCH estimated cancer cases and the consolidated incidence of total
water; its detection has been reported at very low levels in banana cancer cases reported for Paraná State in the same period. The small
plantation areas in Costa Rica (van Wendel de Joode et al. 2016). We number of cases attributed to lindane contamination agrees with the low
found a significant positive correlation between the mancozeb trade and incidence of cancer types associated with this substance in Paraná State,

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C. Panis et al. Environment International 165 (2022) 107321

especially lymphoma cases. Despite this, lymphomas are aggressive and Declaration of Competing Interest
lethal tumors, with a considerable contribution of environmental risk
factors, which incidence has increased over the years (INCA, 2020). The authors declare that they have no known competing financial
Diuron and Mancozeb-ETU contributed to most of the estimated interests or personal relationships that could have appeared to influence
cancer cases. Diuron has been linked by EPA/IARC as a probable the work reported in this paper.
carcinogen for several cancer types, such as kidney, urinary tract, and
lung tumors. Previous studies have reported the occurrence of acute Acknowledgements
lymphoblastic leukemia following maternal exposure to diuron (Park
et al., 2020), indicating that it can be transferred by the human placenta Research in the Lemos lab is supported by grant 5R01ES027981. JC
to the fetus (Mohammed et al., 2018). A strong correlation was found was supported by a Lemann Foundation Fellowship. Carolina Panis was
between the calculated cancer cases due to diuron and the total number supported by grants from Conselho Nacional de Desemvolvimento
of cancer cases reported by the INCA. The same was found for bladder Científico e Tecnológico (CNPq Chamada CNPq/MCTI/FNDCT Nº 18/
cancer, which is the sixth most common cancer in men in the state of 2021 and Chamada CNPq Nº 4/2021 - Bolsas de Produtividade em
Paraná. Pesquisa - PQ) and Coordenação de Aperfeiçoamento de Pessoal de Nível
Finally, a significant correlation was found between the sum of the Superior (CAPES, Professor Visitante no Exterior Júnior - Edital nº 01/
11 pesticide-attributable cancer cases and consolidated cancer cases 2019 - Seleção 2019).
reported by INCA in the same period. Although it is difficult to estimate
the impact of pesticide mixtures on human cancer development, our Appendix A. Supplementary material
analysis indicated that benchmark cancer risk estimation can be a
reasonable way to assess this situation. Supplementary data to this article can be found online at https://doi.
org/10.1016/j.envint.2022.107321.
5. Conclusions
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